Project 3: The metabolomics of tissue injury and hemorrhagic shock ABSTRACT:Tissue injury and hemorrhagic shock (HS) deprive cells of oxygen and delay waste removal, provoking biochemical adaptation to promote cellular survival. The loss of equipoise immediately potentiates trauma induced coagulopathy (TIC) and inflammation, acutely impacting morbidity and mortality. Investigation has spanned decades, but the precise metabolic response to tissue injury and HS remains undefined. Mass spectrometry based (MS)-metabolomics for the study of trauma allows enhanced understanding of the consequences of a rapidly evolving metabolic state following organ-specific injury patterns and varying degrees of hemorrhagic shock. In addition to the simultaneous measure of hundreds of analytes, heavy-isotope labeling experiments, in animal models, define dynamic alterations in primary metabolic pathways, directing testable hypotheses for specific treatment targets translatable to patient care. Novel metabolomics stimulate new hypotheses within areas of longstanding investigation, such as bacterial metabolites as mediators of acute pathology following gut ischemia/reperfusion. Collaborative, tiered analyses of metabolomic details confirm the responses contributing to deadly post-injury systemic consequences, such as TIC and hyperfibrinolysis. Distinct metabolites then become targets for metabolomic-based resuscitation (MSR), aimed at improving immediate post-injury survival, vs. conventional resuscitation. We hypothesize Tissue injury and hemorrhagic shock instigate discrete metabolic changes that cause systemic pathology. MSR will improve early morbidity and mortality after injury by preventing these metabolic consequences. Specific Aim 1. Delineate metabolic responses to organ-specific trauma and HS. Evaluate the efficacy of conventional resuscitation in preventing post-injury metabolopathies that cause systemic pathology. Specific Aim 2. Design metabolomic-based systems resuscitation (MSR) strategies supporting protective adaptations and correcting metabolopathies following polytrauma and HS. To compare post-shock physiologic outcomes between MSR and conventional resuscitation strategies. Specific Aim 3. Investigate the contribution of gut bacterial metabolites to post-shock cell energetics, coagulopathy, inflammation and distal organ injury. Impact: Discrete metabolopathies associated with organ-specific injury, shock, the gut microbiome and the metabolic response to resuscitation strategies. In-vivo isotope labeling provides description of unrecognized metabolic mechanisms and will support novel resuscitation strategies, to be administered in the field, that prevent TIC, hyperfibrinolysis and cardiopulmonary collapse, thereby improving trauma patient survival.